The great Roman natural scientist Gaius Plinius Secundus (Pliny the Elder) in his comprehensive study, circa 60 AD, first described a most potent Indian Ocean sea hare of the genus Dolabella. (The Romans first designated Mollusca of the family Aplysidae as sea hares because of the similarity between the ears of a hare and the auriculate tentacles of these gastropods). However a consideration of the potential of the Indian Ocean Dolabella with respect to modern medical problems is only of recent origin. (See U.S. Pat. Nos. 4,414,205, Nov. 8, 1983, Dolastatins 1-3; 4,486,414, Dec. 4, 1984, Dolastatins A and B; and 4,816,444, Mar. 28, 1989, Dolastatin 10).
The dolastatins may correspond to the potent D. auricularia constituents (See: 1969 Ph.D. dissertation of M. Watson. U. of Hawaii, "Some Aspects of the Pharmacology, Chemistry and Biology of the Midgut Gland Toxins of Some Hawaiian Sea Hares, especially Dolabella auricularia and Aplysia pulmonica", University Microfilms Inc., Ann Arbor, Mich.)
The biological properties exhibited by the Dolabella auricularia have been pursued for centuries but it was only in 1972 that this laboratory found Indian Ocean specimens of this captivating sea hare which yielded extracts that proved effective (over 100% increase in life span) against the U. S. National Cancer Institute's (NCI) murine P388 lymphocytic leukemia (PS system). Subsequently, the Cancer Research Institute at Arizona State University, Tempe, Arizona succeeded in isolating ten new (and powerful) cell growth inhibitory and/or antineoplastic peptides which were designated dolastatins 1 through 10.
Of the early work, dolastatin 1 was found to be the most active (lowest dose) antineoplastic substance (33% cure rate against the NCI murine B16 melanoma at 11 .mu.g/kg) known in its time. Because of the dolastatin's potency, the sea hare seems to require only vanishingly small quantities (about 1 mg each from 100 kg), making isolation and structural elucidation of these peptides exceptionally challenging. Later another substance was isolated and determined to be a unique linear pentapeptide and was demominated "dolastatin 10". This substance was the most important Dolabella auricularia antineoplastic constituent located as it appeared to be the most active (lowest dose) antineoplastic substance found up to its time. In practice, dolastatin 10 showed a 17-67% curative response at 3.25-26 .mu.g/kg against the National Cancer Institute ("NCI") human melanoma xenograph (nude mouse), 42-138 % life extension at 1.44-11.1 .mu.g/kg using the B16 melanoma and 69-102% life extension at 1-4 .mu.g/kg against the PS leukemia (ED.sub.50 =4.6.times.10.sup.5 .mu.g/ml). In contrast, dolastatin 14 is strongly active against NCI's P388 lymphocytic leukemia (PS System) (See: Schmidt et al, Experienta, 1978, 37, 659-660) cell line with an ED.sub.50 of 0.0018 .mu.g/ml. The PS System is generally accepted as an excellent predictor of activity against various types of human cancer (See: Vendetti et al, Lloydia, 30, 332 et seq (1967) and references cited therein).